Nucleoside diphosphate kinase (NDPK)/Nm23 family proteins play multiple roles in energy metabolism, proliferation, differentiation, inflammatory responses and tumour invasion. Among these proteins, only NDPK-D (NME4) is located in the mitochondrial luminal space and the inner mitochondrial membrane. NME4 shows high affinity for cardiolipin (CL) and facilitates its redistribution to the outer mitochondrial membrane (OMM), which leads to mitophagy and inflammatory regulation. Here, we demonstrate that NME4 can regulate the type I interferon pathway by modulating the TLR3-TRAF6-IFN axis. NME4 deficiency promotes the degradation of TRAF6 and impairs the phosphorylation of p65 and p38. Overexpression of NME4 significantly upregulates the interferon production induced by a TLR3 ligand. However, when the NEM4 signal peptide for mitochondrial localization is deleted, the regulation of IFN production is abolished. We demonstrate that NME4 deficiency-mediated suppression of interferon production is rescued when ATG5 is knocked down following TLR3 stimulation, suggesting that NME4 is able to regulate interferon production through the autophagy pathway. Furthermore, influenza A virus-infected NME4 knockout mice showed higher mortality, which was associated with reduced interferon production compared to that in wild-type mice. Taken together, our results indicate that NME4 plays an important role in regulating TLR3-mediated interferon production.
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